Clinical effect of pharmaceutical products using communication tool integrated with compound of several pharmaceutical products

ABSTRACT

A method of treating a respiratory disorder with a combination of substances in combination with a computer program configured for: providing a patient with sets of questions adapted to the combination and to the substances in the combination; subjecting the answers to the sets of questions to functions, thereby generating patient specific feedback; and providing the feedback to the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/160,519 filedOct. 15, 2018 which was a continuation of U.S. Ser. No. 14/417,265 filedJan. 26, 2015, which was a national stage application, filed under 35U.S.C. § 371, of International Patent Application No. PCT/SE2013/050896filed Jul. 12, 2013, which claims priority to SE application No.125089-3 filed Jul. 24, 2012. Each of the previously noted applicationsis hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the field of improving the usage andclinical efficacy of pharmaceutical products in clinical practice,improving health situation of patients, where a combination ofpharmaceutical products is one component in the combined product and acomputer application is another.

BACKGROUND

Today pharmaceutical products on the market are powerful productssolving health problems of the patients. However, most often they solvejust a specific problem or symptom of the patient, i.e. a limited partof the patient needs; meanwhile the patient experiences a wider complexsituation with several other issues and symptoms due to their illness.There is a need for a broader and more profound solution for asignificant number of patients. This is especially the case for severaltherapy areas such as the cardiovascular, the diabetes, the chronicpain, the oncology, the respiratory and the CNS areas and in particularfor patients with multiple diagnoses.

Today a lot of patients, especially the elderly with multiple and severediagnoses, have several different drugs where each drug should addressone or a few of the patient's symptoms. The possibility to evaluate ifthe drugs are clinically efficient, as well as optimized for thecircumstances of the patient, and especially not causing any safetyconcerns, are in most cases missing. A lot of drugs interact with eachother often causing negative health effects for the patients andsometimes critical situations. Today a lot of patients are forced toemergency healthcare visits due to unsuitable medication.

Today drugs on the market are thoroughly tested with regard to theirclinical affect and safety during extensive clinical trials before theyare approved for marketing by a national or regional Medical ProductsAgency, such as EMA in Europe or FDA in the U.S. In most cases, however,there are no verifications, or clinical trials, evaluating the situationof the patients in real clinical practice concerning the situation thatseveral patients are taking a mix of multiple pharmaceuticals.

For several diagnoses, according to existing guidelines, a patientshould be prescribed multiple separate pharmaceutical products in orderto solve the complete health problems of the patient. Patients with, forexample, Acute Coronary Syndrome should be prescribed approximately sixdifferent pharmaceutical drugs.

The existing knowledge of drugs that have been on the market for sometime is mostly very well-known due to the performed clinical trials andthe period of utilization of the drugs in clinical practice. Thisinformation is often available for several different actors to utilizefor researching purposes, but not effectively available directly to theindividual patient using the drug.

Today drugs in clinical practice are not possible to individualize tothe circumstances of each specific patient. Instead estimation is doneby the physician each time a drug is prescribed to a patient based uponhis/her knowledge and the presented data from earlier performed clinicaltrials for a specific drug. There is seldom any follow-up of the resultsof the specific patient in clinical practice, and if the patient notthemselves responds in any way to the results of the medication, noaction is done to improve or secure the result of the treatment.

Drugs on the market today are stand-alone products without any supportor connection to the vast amount of data generated during the researchand development phase of the product, as well as the informationgathered during clinical practice, which could be used for simplifyingand optimizing the relation between the patient needs and thepharmaceutical product clinical conditions. The guidance for matchingpatient specific conditions to the use of pharmaceutical products islimited. The support for finding an optimal dosage for a specificpatient is also missing.

One of the major issues to reach an increased clinical effect ofpharmaceutical treatments in clinical practice is to improve adherenceto prescribed medication, see World Health Organisation 2003 Report:Adherence to long-term therapies; Evidence for action: (available athttp://whqlibdoc.who.int/publications/2003/9241545992.pdf)

Due to the lack of adherence to medication the results of pharmaceuticaltreatments in clinical practice have difficulties in reaching similarresults of clinical effect as the ones made in clinical trials duringthe development of the pharmaceutical products.

In regulations from FDA and EMA focus on patient safety and follow-up ofside effects, as well as possible adverse events, regardingpharmaceuticals is crucial. In clinical practice, however, this isdifficult to achieve and the patient is mainly responsible with littleor no support to accomplish it properly.

Even though the safety concerns of medications are directly related tothe specific pharmaceutical products, today there are very limitedfeatures, or no features, at all integrated with the pharmaceuticalproduct aiming at improving the patient safety concerns of the product.It is up to the patients themselves to handle the safety issues.

Medical devices enhancing the therapeutic effect of drugs are known. Forinstance, specifically designed inhalers are used to administer variousanti-asthmatic drugs and implantable devices have been used forcontrolled release of anti-cancer drugs.

Patient compliance and monitoring systems are known in the art, e.g.WO02095352. Such systems are focused on monitoring patient complianceand reporting to the medical practitioner and the patient how thetreatment is progressing. The system disclosed in WO02095352 is relevantfor a certain condition (menopause) and a general therapy (hormonereplacement therapy). It is not specifically adapted for a particularpharmaceutical product.

Different types of e-health applications are existing knowledge, as wellas, the positive clinical effects of such systems. This kind ofapplications is focused on improving the health situation for thepatient in general independent of any specific pharmaceutical. This kindof system has a large interest within clinical practice, but the broadusage of such systems today within healthcare is absent.

SUMMARY OF THE INVENTION

A central aspect of the invention is a combination product where acomputer program product is integrated with two or more includedpharmaceutical products through a connected question-analysis-feedbackmodel (QAFM). A physician will be able to prescribe the combinationproduct, with the following included components; the computer programproduct, the QAFM and the pharmaceutical products, to patients.

This aspect of the invention can be described as a combination of Nsubstances, wherein N>1, with pharmaceutical activity against at leastone medical condition for use in a treatment of said at least onemedical condition in combination with a computer program product (110)comprising instructions causing a computer to perform a methodcomprising the steps

-   -   providing a patient (102) with a set of questions (107)        according to a question schedule, wherein said set of questions        is adapted to said combination of substances;    -   providing a patient with N sets of questions (106 ₁, -106 _(N))        according to N question schedules, wherein each set of questions        is adapted to one of the substances in said combination;    -   collecting answers to said sets of questions from said patient;    -   subjecting the answers to said set of questions (107) adapted to        said combination of substances to a set of functions (109),        thereby generating a first patient specific feedback        information;    -   subjecting the answers to said sets of questions (106 ₁, -106        _(N)), each adapted for one of the substances in said        combination, to n sets of functions (108 ₁, -108 _(N)), thereby        generating a second patient specific feedback information;    -   providing said first and second patient specific feedback to the        patient; and    -   optionally extracting information from said answers and        providing said information to a database adapted for collecting        information during clinical use of said combination of        substances.

Preferred embodiments of this aspect are detailed in the dependentclaims.

The purpose and the effect of the combination product is to enhance andto improve the treatment of the patients, achieving improved clinicaleffect, safety and quality of life to the patients in clinical practice,compared to using just the particular pharmaceutical productsthemselves. The purpose and the effect of the invention are fulfilled byseveral different aspects.

According to the invention, several pharmaceutical products areintegrated, in the combination product, through a QAFM, where eachincluded pharmaceutical product in turn is integrated with an adaptedquestion-feedback model (QFM). The specific QFM is developed and adaptedbased on the clinical characteristics of one single specificpharmaceutical product. The QAFM is adapted to each and multipleincluded QFM, and hence, each included pharmaceutical product. The QAFMis related and adapted to the combination of the included QFM:s.

One feature of the invention is that the QAFM, and the QFM:s, aredeveloped to improve the clinical effect, the safety concerns, and thequality of life of patients, based on the clinical characteristics ofthe included pharmaceutical products and the circumstances andconditions of every specific patient.

According to the invention, the QAFM will enable an optimization andindividualization of the different included components, such as theQFM:s, the included pharmaceutical products, the adherence and theactual dosage, based upon each specific patient's circumstances,capability and behaviour, in order to achieve an improved clinicaleffect, safety and quality of life. The optimization andindividualization will be performed based upon the answers from eachspecific patient in relation to existing relevant information regardingclinical use of the actual pharmaceutical products and will be done bythe QAFM and the computer program product. For example, a conclusion onsuch an evaluation can be that a particular patient shall increase thedosage of one pharmaceutical product and remove another. The objectiveis to achieve concrete increased health for each individual based upontheir specific circumstances.

One aspect of the invention concerning the optimization andindividualization is to continuously evaluate the health situation ofeach specific patient based on the input from the patient, concerninghis/her behaviour and specific circumstances, in relation to theexisting relevant clinical information in clinical studies or clinicalpractice regarding the used pharmaceutical products, the actualadherence to the pharmaceutical products, the interaction between theincluded pharmaceutical products, the selected dosing regimens andpossible other aspects of the QAFM. Based upon this evaluation the QAFMwill respond to the defined users, such as the patients themselves andthe healthcare personnel, about the status of the health of the patientand recommended actions, in order to improve the clinical effect, toimprove the safety or to improve the quality of life. In this way, theQAFM could, for example, respond with feedback to the relevant usersthat either a problem has occurred, such as an interaction between twodrugs, or a positive change has happened. If a change in the usedpharmaceutical products is recommended, it would most probably need tobe handled by a physician.

One aspect of the invention is that the QAFM will be able to evaluatethe best QFM for each specific patient based upon the specific patient'sbehaviour and clinical needs in relation to substance combinationspecific data in clinical studies and clinical practice. The type offeedback will be evaluated, as well, in order to identify and improvethe feedback, given to the specific patient. The objective is to use thetype of feedback achieving improved clinical effect, safety and qualityof life.

One aspect of the invention is that the development of the QAFM shouldbe dependent on each included QFM. It will be central that the QAFM willbe related to the content and the characteristics of the included QFM:sand pharmaceutical products.

Another aspect and central component of the invention is that the socialbehaviour and psychological well-being could be central aspects withinthe QAFM and the QFM:s. The possibility to interact with both healthcarepersonnel, as well as other patients, will be an aspect of theinvention.

One aspect of the invention is that the computer program product and theQAFM should be able to individualize the treatment to a patient'sspecific circumstances and personal objectives.

Another central aspect of the invention is to enable and to improvepatient safety. The invention will enable early warnings for each userof the invention of possible security alerts concerning the includedpharmaceutical products and possible interactions between them, andpropose recommended actions to take. This will enable an improvedpatient safety concerning prescriptions of pharmaceuticals.

One aspect of the invention is that the existing, available knowledgeconcerning pharmaceutical products forms a fundamental knowledge-basefor the development of adapted QFM:s, and QAFM.

One aspect of the invention is that it will be possible for a physicianto prescribe a computer program product with different pharmaceuticalproducts included components within the QAFM, instead of just separated,stand-alone pharmaceutical products. The physician will be able toprescribe a product more fully addressing the problems of the patient'stotal health situation.

Another aspect of the invention is that a product based on the inventionwill be able to develop and adjust in order to match the guidelineswhich healthcare is using within a specific therapeutic area. Forexample, within several cardiovascular diseases guidelines for patientsinclude both multiple identified drugs and recommendations regardingcertain life-style changes. A product based on the invention can includevariants of these components, making it easier and more efficient forboth patients as well as healthcare personnel.

The invention is primarily intended for therapeutic areas in whichpatients with multiple diagnoses have been prescribed severalpharmaceuticals and consequently patient safety is a concern.

Large amounts of data on a pharmaceutical product are collected duringclinical trials performed by the manufacturers of the pharmaceuticalproduct. The amount of data is generally too large to be kept in mind ofa single person and is summarised by various methods into guidelines foruse, such as dosage regimens, counter-indications and risks for sideeffects and adverse events.

A medical physician prescribing a product based on the invention, aswell as a pharmacist selling a prescription or non-prescription of theinvention-based product, will have certain knowledge of the product andthe included pharmaceutical products. In some countries lacking adequateregulations, pharmaceuticals may even be provided to patients by personswithout proper pharmaceutical or medical training. The providingperson's knowledge of pharmaceutical products is based mainly on themanufacturer's information, which in turn is based on the summaries ofthe amount of data collected during clinical trials. The providingperson may further be highly specialised in the use of a product, suchas a researcher with a special interest in the product and the diseaseit is aimed to treat, but is more likely to be a practitioner who on adaily basis treats patients with very disparate conditions and diseases.Such a physician needs to be well informed about hundreds of differentpharmaceutical products. This entails that certain information, such asrecently discovered information or possible interactions, on theproduct, may be overlooked or unknown to the providing person.

The present invention is based on the realization fact that the integralcombination of the pharmaceutical products used, and a specificallyadapted system for receiving information from a user of thepharmaceutical products and providing feedback to said user can be usedto achieve a number of benefits in clinical practice. In this way, apatient using the integrated package of the pharmaceutical products, andthe developed QAFM, can directly benefit from the entire body ofknowledge, such as clinical data, related to the pharmaceutical productsin the possession of the manufacturer or supplier of the invention-basedproduct, in addition to the information provided by the medicalpractitioner and/or pharmacist providing the product package. In thissense, the present invention aims to provide a technological support tothe patients in order that they benefit from the most recent informationabout their medication, adapted to their specific situation.

One aspect of the invention is a combination product, or a kit-of-parts,comprising the drug(s) in question and a computer program productcomprising instructions causing a computer to provide the patient withthe questions, receiving answers to the questions, analysing andprocessing the answers and providing feedback to the patient.

One aspect of the invention is a method of treatment of a medicalcondition with the substances having pharmaceutical activities againstsaid medical condition(s) in combination with a computer program productcomprising instructions causing a computer to provide the patient withthe questions, receiving answers to the questions, analysing andprocessing the answers and providing feedback to the patient.

One aspect of the invention is to improve the treatment of the patient,based on the invention, where the usage, including dosage andadministration, of the included pharmaceutical products are related tothe usage.

The above three aspects of the invention shall be considered asequivalent unless specifically indicated otherwise. In particular, thecharacteristics of the pharmaceutical products and computer programproducts are the same in all three aspects.

Another aspect of the invention is to make clinically relevantinformation obtained during clinical use, i.e. clinical trials orclinical practice, of the pharmaceutical products come to the benefit ofindividual patients in a more efficient way. This is realized bycontinuously updating the question-analysis-feedback model, the QAFM,implemented in the Computer Program Product by including thereininstructions causing the computer to perform a method comprising thesteps

-   -   a) providing a patient and optionally a further respondent with        sets of questions according to a question schedule, wherein said        sets of questions are adapted to the combination of substances        and/or to at least one of the substances in said combination;    -   b) collecting answers to said questions from said patient and        optionally said further respondent;    -   c) subjecting said answers to a set of functions specific for        the sets of questions and the pharmaceutical product thereby        generating patient-specific feedback information;    -   d) providing said feedback information to the patient and        optionally to the further respondent;    -   e) extracting information from said answers and providing said        information to a database adapted for storing information        collected during clinical use of said combination of substances;    -   f) providing information stored in said database to a reviser        subjecting the sets of questions and/or the sets of functions to        a revision based on said information stored in said database;    -   g) obtaining a revised set of questions and/or a revised set of        functions from said reviser; and    -   h) repeating steps a)-g).    -   i)

The information on which the revision is based can be collected from theindividual patient or from more than one patient, preferably at least50%, such as at least 75% or substantially 100% of patients, clinicallyusing said substance(s) in combination with said computer programproduct. Revision of the set of functions may include a revision of thefeedback information and type of feedback given to the patient.

The reviser performing the revision may be one or more persons skilledin analysis of clinical data and drafting clinical guidelines, such as ateam of medical doctors, clinical statisticians and/or pharmacists. Itmay also be a suitable computer-implemented expert system or set ofrevision functions. Such a set of revision functions may includecomparison of patient parameters and/or patient trend lines withreference parameters and reference trend lines calculated from theinformation collected from more than one patient, preferably at least50%, such as at least 75% or substantially 100% of patients, clinicallyusing said substance(s) in combination with said computer programproduct. Alternatively, the reference parameters and reference trendlines are calculated from information collected only from comparablepatients, e.g. patients having the same or similar age, life-style,clinical status, clinical history, sex, ethnicity etc.

The specific information which the database is adapted to store providesthe provider of the invention the possibility to collect relevant datafrom a significant number of patients using the invention in clinicalpractice and iteratively improve and further adapt the sets of questionsand sets of functions to real-life conditions.

One aspect of the invention is to enhance the relation between thespecific conditions for each particular patient, both concerningbehavioural and physiological aspects, with the clinical conditions forthe specific pharmaceutical products concerning used dosage, identifiedside effects and adverse events, and clinical effect in order to improveindividualization. This may be done by including existing clinicalresearch data for the pharmaceutical product(s) in the QAFM, andseparate QFM:s, and integrated data of the invention. Theindividualization may be done in several different ways, including forexample an updated QAFM concerning any recommendations of changed dosageor administration or recommendations of changed pharmaceutical products.

One aspect of the invention is to enhance patient adherence to theprescribed dosages or administration regimens and to enhance theclinical efficacy of the included pharmaceutical products. This may bedone by including questions on the actual administration; actual dosage;perceived and/or measured therapeutic effects; the relevant life-stylefactors of the patient; test results and/or perceived quality of lifeand providing the patient with feedback correlating the positive effectsof the pharmaceutical products, and/or the absence or low prevalence ofnegative effects, with adherence to the prescribed dosage oradministration regimen and life-style factors.

One aspect of the invention is to give the user early indications of theoccurrence or development of a possible adverse event and/or sideeffect, by including questions relating to the occurrence or developmentof a possible adverse event and/or side effect of any of the includedpharmaceutical products. This increased awareness of adverse events andside effects results in enhanced protection of patients from adverseevents and side effects. This may enable an increased patient safety,which is demanded from authorities like EMA and FDA on pharmaceuticalproducts. This may enable early introduction of pharmaceutical productswith an incomplete safety profile on the market, since it allows formaking each user of the pharmaceutical product aware of the occurrenceor development of a possible adverse event and/or side effect and alsofacilitates that this may be reported directly to medical staff. It mayalso enable re-introduction of products withdrawn from the market due toan unacceptably high frequency of adverse events or side effects bymaking each user of the pharmaceutical product aware of the occurrenceor development of a possible adverse event and/or side effect at anearly stage.

One aspect of the invention is that the healthcare personnel easily willbe able to get an overview report about the health situation of aspecific patient, including the aspects of the QAFM, the QFM:s and theincluded pharmaceutical product(s), and analyzed recommendations of howto improve the clinical effect, safety or quality of life.

One aspect of the invention is that the question-feedback models, QFM:s,are central and necessary parts of the question-analysis-feedback model(QAFM).

One aspect of the invention is to enhance the patient's quality of life.

The computer program product is preferably adapted to be installed on ahandheld device, such as a mobile telephone, a smart phone, a PersonalDigital Assistant (PDA), tablet computer or similar devices. Thecomputer program product may also be installed on a remote computer,e.g. a. server, web or cloud-based service, and accessible to the userthrough a computer such as a handheld device, a stationary computer, alaptop or the like. In such a case the feedback is also preferablyprovided through the same device.

Other aspects of the invention are the computer program product itselfand the method performed by the computer program product.

Other aspects of the invention are as provided in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the combination product and the structure and usageof two QFM:s (103 ₁, 103 ₂) adapted to specific pharmaceutical products(100 ₁, 100 ₂), in relation to one QAFM (110) and the patient (102). 107denotes the set of questions of QAFM and 109 the set of functions(analysis part) of QAFM. 112 denotes the computer platform used forinteraction with the respondent.

FIG. 2 illustrates the two QFM and the QAFM when adding a furtherrespondent 102′.

FIG. 3 illustrates when the further respondent is answering thequestions on a separate computer platform 112′.

FIGS. 4A-4C illustrate examples of question presented in the mobilephone and example of feedback. (4A) Numeric question; (4B) Feedbackgraphs with patient specific data; (4C) Feedback graphs with patientspecific data, user interface on a regular computer.

FIG. 5—Development of the model

FIG. 6—Overview embodiment of the model in the study

FIG. 7—Schematic view of Set of Questions and Feedback Information

FIG. 8—Schematic view of the question schedules

FIG. 9—Overview technical implementation of the CPP

FIG. 10—Example of a possible patient feedback graph

DEFINITIONS

All words and terms used in the present specification are intended tohave the meaning usually given to them in the relevant art. However, forthe sake of clarity, a few terms are specifically defined below.

The term “set of questions” is a questionnaire with predeterminedquestions or items shown to a respondent to get answers for feedbackpurposes. The questions within the set preferably have a limited numberof possible answers, such as yes/no; scale 1-10; multiple choice; etc.The questions may however also have an undefined number of answers, suchas a value of a test parameter (e.g. blood pressure, blood glucoselevel).

The questions in the set of question are posed to the respondentaccording to a certain regimen or schedule. This is denoted a “questionschedule” or “question regimen” in the present application. These termsare intended to be equivalent if not otherwise indicated.

The term “set of functions” means a set of functions that can be appliedto the answers to a set of questions to extract specified informationand generate feedback based on the answers.

The combination of a set of questions and a set of functions is referredto as a “question-feedback model”, sometimes abbreviated “QFM”.

The combination of several included QFM:s, as well as the combination ofanother set of questions, another set of functions and the type offeedback, is referred to as a “question-analysis-feedback model”,sometimes abbreviated “QAFM”.

The QAFM and the QFM:s could together, as a group, be denoted as the“model”.

That a set of questions is “specific” to a certain pharmaceuticalproduct shall be construed to mean that it comprises questions that areapplicable and clinically relevant to the pharmaceutical product. Theindividual questions, and the set of questions in total, are preferablymore applicable and clinically relevant to the pharmaceutical product inquestion than to any other pharmaceutical product.

The term “respondent” is used to denote the individual responding to aquestion.

The term “patient” is used to denote the individual using thepharmaceutical product.

The terms “computer application” and “computer program product” shall beconsidered equivalent unless specifically indicated otherwise.

The terms “pharmaceutical product” and “medical product” shall beconsidered equivalent unless specifically indicated otherwise. Theseterms refer to pharmaceutically acceptable compositions ofpharmaceutically active substances (drugs) intended for administrationto a patient.

The term “side effect” means a secondary and potentially adverse effectof a drug or treatment.

The term “adverse event” means an adverse outcome that occurs during orafter the use of a drug or other intervention but is not necessarilycaused by it.

“Clinical use” shall be construed as the use of the pharmaceuticalproduct and/or the life style factor by individual subjects. It includesthe use of the pharmaceutical product in Phase II, III and IV clinicaltrials and the use of the product in patients in clinical practice(sometimes referred to as real life).

“Clinically relevant information” shall be construed as informationrelevant to the clinical characteristics of a pharmaceutical product,e.g. on effect, side effects, counter-indications, metabolism etc. Suchinformation is extensively collected during clinical trials.

DETAILED DESCRIPTION OF THE INVENTION

The main aspect of the present invention is a combination productcomprising two or more pharmaceutical products and a computer programproduct comprising instructions to perform a method comprising the stepsof providing a defined set of specific questions to the user, collectinganswers to the questions and analysing, transforming and processing theanswers by way of a defined set of specific functions to generatefeedback to the patient.

By adapting the combination of the set of questions and the set offunctions, which combination is hereinafter called the“question-feedback model”, to be adapted to one pharmaceutical product,and optionally the therapeutic indication and/or prescribeddosage/administration regimen, it is possible to achieve clinicalimprovements in the therapeutic effect of the pharmaceutical product andquality of life for patients. By adapting the combination of two, ormore pharmaceutical products, and the corresponding adapted QFM:s, intoa model called the “question-analysis-feedback-model” (QAFM), it ispossible to achieve an even higher, unexpected and significantimprovement in the therapeutic effect of the pharmaceutical products andquality of life for patients. Without being bound by theory, theimproved therapeutic effect within the area of the includedpharmaceutical products and quality of life, may be due to improvedindividualization concerning patient specific conditions and clinicalaspects of the pharmaceutical products, due to improved adherence by thepatient to the prescribed administration and/or dosage regimen, due toimproved awareness of other factors influencing the relevant conditionbeing treated with the pharmaceutical products, or due to a placebo-likeeffect.

For each combination of the computer program product and onepharmaceutical product a question-feedback model is developed andadapted to the specific characteristics of the pharmaceutical productand the behavior of the patients within the actual therapeutic area(s).The development of the question-feedback model follows the same generalrules for different types of pharmaceutical products, but the specificquestion-feedback models will be different due to the characteristics ofthe pharmaceutical product and its clinically relevant information.

For each combination of several pharmaceutical products and the adaptedQFM(s), a QAFM is developed and adapted to the specific characteristicsof the included pharmaceutical products and the behavior of the patientswithin the actual therapeutic areas(s). The development of the QAFMfollows the same general rules for different types of pharmaceuticalproducts and therapeutic areas, but the specific QAFM will be differentdue to the characteristics of the pharmaceutical products, itsclinically relevant information and the patient behavior.

The question-feedback model, QFM, comprises the following parts, ofwhich all are adapted for the clinical effect of the pharmaceuticalproduct:

-   -   A set of questions    -   A set of functions    -   The type of feedback

The set of questions is implemented in a questionnaire giving therespondent the ability to choose any of a number of possible answers toeach question or enter a number representing a test value.

The questions may relate to the following, the list being illustrativeand non-exhaustive:

-   -   Side effects and adverse events, such as adverse drug effects    -   Adherence to dosage and/or administration regimen, such as if or        when the pharmaceutical product has been administered; or which        dose was administered.    -   Symptoms, such as stiffness; swelling of limbs or joints;        headache; pain; blood in excrement; incontinence; fever;        urticaria; rashes; skin irritation; itching; dryness of mouth;        shortness of breath; coughing; sneezing; rhinitis; anxiety;        irritation; restlessness; dizziness; fatigue symptom    -   Dietary intake, such as meal size; meal frequency; type of diet;        satisfaction with diet    -   Exercise, such as type, duration, frequency or avoidance of        physical exercise    -   Mood, such as if the respondent feels happy, sad, depressed,        anxious, restless, etc.    -   Sleep, such as if the patient has slept well; duration or        quality of sleep [Ref: Torbjörn Åkerstedt; The importance of        sleep for health and work]    -   Use of tobacco, alcohol and other drugs, such as type and amount        of use; addiction; intention or inclination to quit use;        progress or lack of progress in cessation    -   Stress, such as perceived stress level; amount of personal        quality time or spare time; amount of family quality time;        stress at work    -   Body functions, such as the function of the gastrointestinal        system; mental capacity, muscle strength/weakness;        cardiovascular capacity; physical capacity    -   Treatment, such as if the treatment perceived is working well;        motivation to start or continue treatment    -   Quantitative test results, such as blood pressure; body fluid;        blood tests or excrement analysis results; body weight; Body        Mass Index; pulse etc    -   General, such as quality of life; feeling of support from        family, friends, caregiver

The questions within the set preferably have a limited number ofpossible answers, such as yes/no; Visual Analogue Scale (VAS); Likertscale; multiple choice, including symbols (such as “happy face” and “sadface” to capture mood); etc. However, the questions may also have anundefined number of answers, such as a value of a test parameter (e.g.blood pressure, blood glucose level, body temperature, weight) or freetext.

Generally, the questions are posed to the patient using the inventionbased product because only the patient has the true first-hand knowledgeof his/her situation. However, in addition to questions posed to thepatient, further questions may be posed to other respondents. These mayinclude family members, relatives or other persons close to the patient.This may be particularly useful for pharmaceutical products used intreatment of psychiatric disorders where the patient's assessment ofhis/her situation may be incomplete and observations made by anotherperson may be valuable. Questions to be answered by other respondentsmay belong to the same set of questions as those answered by thepatient, but may be implemented in a separate questionnaire.

The specific questions and invitations given to the respondents and thetype of questions are adapted to the specific characteristics of thepharmaceutical product and the behavior of the patients within thetherapeutic area in order to optimize the clinical effects.

When defining the actual questionnaire it is preferable to developquestions to the respondent in order to identify possible upcomingadverse events, or indications of adverse events, as well as possibleupcoming side effects with the purpose of increasing patient safety ofthe included pharmaceutical product.

In addition to the set of questions, also a regimen for asking therespondent questions should be developed, including which questions arecompulsory to answer, optionally before or after a certain time orwithin a certain time interval; the questions which may be leftunanswered; at what time of the day the questions will show up for therespondents to answer; with what frequency the questions shall show upetc. The regimen can be static over time but also change, e.g. thefrequency of questions can decrease with time or change depending on therespondent's answers.

In addition to the above described questions it may be advantageous toinclude messages, which cannot be answered, to the respondent. Suchmessages may include recommendations, suggestions or informationintended to motivate the respondent, e.g. to continue the prescribeddosage regimen although symptoms have disappeared or are lesspronounced.

It may furthermore be advantageous to adapt the set of questions andmessages and the regimen for asking the questions and providing themessages with regard to cultural differences and the language of theuser. Principles for the translation and cultural adaptation process forPRO measures have been described (Wild D, et al., Value Health 2005;294-104) and may be adapted to the present invention by the skilledperson.

The question-feedback model, QFM, further comprises retrieving answersfrom the respondents in a predefined format suitable for input into theset of functions for generating feedback.

The question-feedback model, QFM, further comprises a set of functionsto generate patient-specific feedback based on the answers of therespondent or respondents. These functions may comprise:

-   -   Calculations resulting in a realistic target for a specific        patient to achieve. The target could be based on information        given from the results from earlier clinical trials concerning        the pharmaceutical product or other existing relevant        information from clinical practice. Then the target can, for        example, be illustrated as a continuous graph of the predicted        development for the patient, given that the prescribed        administration or dosage regimen is followed. The illustration        of this continuous graph would vary between different        pharmaceutical products and therapeutic areas. In some areas it        will illustrate the improvement of the condition whereas in        other areas, for example, COPD (Chronic Obstructive Pulmonary        Disease) where patients slowly feel worse, it will illustrate        the lack or relative slowness of feeling worse.    -   Calculations of future predictions for a specific pharmaceutical        product and patient, based upon earlier answers from the patient        and results from clinical trials and answers from other patients        in clinical practice using the actual pharmaceutical product,        for example external web and data sources. These future        predictions can, for example, be several predictions for each        patient, based upon different circumstances in the shape of how        the patient changes his/her behavior. An example of this will be        if the patient increases the adherence to the specific        pharmaceutical product the patient and thereby will develop in a        more positive way concerning specific symptoms of the disease.    -   Knowledge and rules using, for example, methods for Computer        Adaptive Testing and Item Response Theory including the adapted        databank with the purpose of optimal individualized and        personalized medicine. This can, for example, result in an        individualized questionnaire for each patient based upon their        own characteristics and behavior.    -   Calculation of trend lines based upon the specific        pharmaceutical product and the answers given by the patient.    -   Rules and thresholds for defining when to give notifications        concerning the pharmaceutical product and different kind of        issues, e.g. possible adverse events, possible side effects,        change dosage regimen, possible interaction of other prescribed        drugs etc. These have to be carefully developed and have to take        notice of possible combination between different questions, the        evolvement of the answers from patients over time, other        possibly used medication, etc.

Patient-specific feed-back is generated by the above described set offunctions based on answers supplied by the patient. The feedback may beprovided through any medium favorable to the patient, e.g. through awebsite, a handheld device (mobile phone, smart phone, tablet computer,PDA, etc), paper, voice, e-mail, fax, SMS, or corresponding type ofmessage etc.

Examples of feedback are:

-   -   Graphs illustrating the answers given by the patient on        different selected questions. The graphs may, among other        things, illustrate how the patient has evolved over time.    -   Illustrating the answers from the patient in combination with        calculated values such as the targets for the patient. The        purpose of this type of feedback is, for instance, to motivate        the patient to continuous improvements.    -   Illustrations of how the patient's health status is evolving in        comparison to the evolvement of earlier patients using the same        pharmaceutical product, for example patients in clinical trials        other existing relevant clinical information from clinical        practice.    -   Illustrations of how the patient's health status can evolve and        the result of it as a future prediction, based upon how the        patient continues to handle his/her health situation and data        from clinical use of the pharmaceutical product. For example,        graphs can be used to show how the patient may evolve if the        patient increases the adherence to the medication of the        pharmaceutical product.    -   The, preferably de-identified, answers from the patient in        relation to calculations based upon information given from other        patients in clinical practice using the pharmaceutical product,        specifically selected for the actual circumstance. The purpose        of this is, among other things, to encourage the patient to        increase his/her personal health status.    -   Message sent based upon notifications from the algorithms. This        can, for example, be messages concerning possible adverse        events, or indications of possible side effects, or possible        conclusions that a new dosage for the actual pharmaceutical        product may be needed, or positive feedback to the patient to        encourage a behavior leading to e.g. better adherence or        increased quality of life. Exemplary messages can include        messages that the used dosage of the pharmaceutical product        ought to be changed, or that the first signs of a side effect        appear to be showing and that the patient should be aware of        these signs. The invention will hence enable a faster change of        used medicines by patients experiencing an adverse event. The        patient can receive messages from the healthcare personnel as        well as through the computer program product, as a result of the        feedback.    -   The questionnaire given to the patient can change based upon the        algorithms for CAT and IRT (see above), or other appropriate        algorithms or computer implemented methods, in order to        individualize the questions for the characteristics of each        patient and the pharmaceutical product.

Optionally, feedback may also be provided to other than the patient,such as the health care staff (e.g. treating medical practitioner ornurse, pharmacist etc.). Such feedback may include:

-   -   Results from notifications from the algorithms, e. g. when an        adverse event or a side effect has occurred. This information        can, for example, be sent to the responsible healthcare provider        and/or authorities such as the Medical Products Agency. The        healthcare personnel will then be able to take appropriate        adjustments. The graphs and illustrations presented above can be        given to the responsible healthcare personnel as well.    -   Results from continuous results in clinical practice based upon        the answers given by the patients. The invention could hence        improve clinical research through continuous follow up of a huge        amount of patients for the specific selected pharmaceutical        products. The information/answers from the patients will be        de-identified and returned to the researching organization. The        purpose is to utilize the enormous information in real clinical        practice in order to develop improved pharmaceutical products        and treatments for patients.

The continuous follow-up of the results from patients will also resultin possibilities for an easy evaluation between different kind oftreatments, both from a medical and an economic perspective.

The question-feedback model, QFM, may be adapted to the specificpharmaceutical product by using the information on the pharmaceuticalproduct available from clinical trials carried out in preparation for anapplication for marketing approval for the pharmaceutical product. Suchtrials are designed to find all relevant information about thepharmaceutical product and that information can be used to design theset of questions with applicable answers, the set of functions forgenerating the feedback from the answers, and the form of feedbackprovided to the patient. The continuous development of the QFM, for aspecific pharmaceutical product, will also take into considerationrelevant knowledge from clinical practice concerning the specificpharmaceutical product, other studies, patient behavior concerning thespecific pharmaceutical product, etc.

Information on the normal effect of the pharmaceutical product can beused to provide the patient with feedback on how he/she achieves abetter or worse effect than normal when using the pharmaceuticalproduct. It may also be used to give the patient feedback on how thetreated condition will have developed if the pharmaceutical product hadnot been used, or used to a different extent than the patient actuallyis using it.

Information on known possible side effects may be used to includequestions giving early feedback on occurrence of side effects, which mayguide the user to change or cease the administration or dosage regimenaccording to guidelines based on the information about the side effects,or to contact the treating physician if advised.

Information on known counter-indications for using the pharmaceuticalproduct may be used to include questions giving early feedback warningfor possible side effects or adverse events. It may be that duringtreatment with the pharmaceutical product the patient contracts acondition which may lead to an adverse event or side effect incombination with the pharmaceutical product. If such risks are known, itis possible to include questions resulting in feedback making thepatient and optionally the treating physician aware of thiscomplication, which may lead to an adjustment or change in treatmentimplying an improved patient safety of the pharmaceutical product.

For example, an earlier registered pharmaceutical product indicated fortreatment of obesity was known to worsen depressions. The majority ofquestions and feedback in a question-feedback model for an obesity drugwould probably focus on diet, physical activity, weight loss and thelike. The inclusion of one or more mood-related questions would howeverbeen able to indicate early if the patient was at a risk of developing adepression which would have been a strong indication to the patient tocease the administration of the actual pharmaceutical product. Thesequestions should have been specifically designed to retrieve relevantinformation on the types of mood-related adverse events or side effectsassociated with the specific pharmaceutical product.

Optionally, additional information not supplied directly by the patientcan be used. This may include:

-   -   Information from performed clinical trials. This can, for        example, be the result of how the included patients in the        clinical trials using the actual pharmaceutical product        responded to the pharmaceutical.    -   Information from other patients in clinical practice. This can,        for example, be the result and answers given by other patients        in clinical practice? using the same pharmaceutical product and        how they respond to the pharmaceutical. Using this information,        a common index of how a huge amount of patients react upon the        actual pharmaceutical product in clinical practice can be        evaluated, for instance.    -   Information from other products and systems, such as        administration systems, laboratory data, personal patient        devices such as watches, heart rate monitors, scales, mobile        phone applications, pedometers, glucose meters, thermometers,        audiometers, inhalers, ultrasound devices, electrocardiography        devices, etc. Such information can automatically be collected by        or transferred to the computer program product by different        means.

For each combination of a specific pharmaceutical product and thecomputer program product a candidate specific question-feedback model,QFM, has to be developed. This candidate model has to be developed basedon all considerations mentioned above.

The development of the candidate question-feedback model, QFM, includesthe following steps:

A suitable set of questions is identified and developed. The intentionis to develop an optimal set of questions and normally this is aniterative process. In this, the following aspects should be considered,as well as the concerns mentioned above describing what is included inthe set of questions.

-   -   The set of questions should be designed based upon the specific        clinical circumstances of the pharmaceutical product concerning        the existence of possible adverse events, possible side effects        and the therapeutic effect.    -   The set of questions should be designed based upon the special        circumstances of the patient category of the actual therapeutic        area.    -   The set of questions should be designed in order to improve the        behavioral aspects of the patients. They should increase the        possibilities for enhanced clinical effect and patient safety of        the specific pharmaceutical product, and the quality of life for        the patients.    -   The questions should be easy to understand and encourage the        patient to answer them.

The suitable and optimal structure type of questions should be used,i.e. VAS, Likert scale, free text, multiple choice, etc.

-   -   The amount of questions should be minimized in order to simplify        for the patients.    -   The proper regimen for asking the respondent questions should be        developed. The following should, for example, be defined:        -   When the questions should appear in the patient's device,            for instance which specific day and what time during the day        -   Which questions that should be compulsory to answer        -   The frequency of how often the questions should appear in            the patient's device    -   Which questions that should be able to individualize, i.e. to        add or remove, and to which extent. For example, some questions        could be able to appear more or less seldom, i.e. changing the        frequency of the question.    -   Whether, and in which way, the set of questions should be        individualized and adopted based upon the patient and the        pharmaceutical product specific clinical conditions. This could        involve how the questions should be answered, selection of        media, etc, with the purpose of improving the clinical effect        and patient safety of the specific pharmaceutical product.

A suitable set of functions is identified and developed. The intentionshould be to develop an optimal set of functions and normally this is aniterative process. In this, the following aspects should be considered,as well as the concerns mentioned above describing what is included inthe set of functions.

-   -   The set of functions should be designed based upon the specific        circumstances of the pharmaceutical product concerning the        existence of possible adverse events, possible side effects and        the therapeutic effect.    -   The set of functions should be designed based upon the special        circumstances of the patient category of the actual therapeutic        area.    -   The set of functions should be designed in order to improve the        behavioral aspects of the patients. They should increase the        possibilities for enhanced clinical effect and patient safety of        the specific pharmaceutical product, and the quality of life for        the patients.    -   The set of functions should be developed based upon which type        of information that is possible to use considering the specific        pharmaceutical product, e.g. if there are information from        earlier clinical trials and/or if information from other        patients in clinical practice, that can be utilized.    -   The set of functions should be developed based upon whether        knowledge and rules from methods using Item Response Theory and        Computer Adaptive Testing, or other appropriate algorithms or        computer implemented methods, are available.    -   The set of functions concerning rules and thresholds, for        example with the purpose of avoiding possible adverse events        and/or side effects, giving positive feedback and optimizing the        dosage regimen, should be developed concerning the circumstances        of the pharmaceutical product, performed clinical trials and the        specific patient population.    -   The set of functions could contain rules of which questions        should be related to specific thresholds, for example if a        threshold is reached by a patient, which questions should then        appear or which type of feedback should be given.    -   The set of functions could contain dependencies between certain        questions and the functionality and rules of the dependencies,        e.g. if a patient answers a specific alternative on one question        another specific question appear, otherwise another question        will appear instead.    -   The set of functions could contain the administration rules        concerning different intervals when specific questions will        appear based on a certain threshold, which could be time or that        a criterion has been fulfilled. An example of this is that        during a first period of time the patient could have a certain        set of questions, and after a certain period of time, which        could be a couple of weeks or months, the set of questions        changes into another version. The set of questions could also be        changed due to a certain threshold has been fulfilled, for        example a certain level of blood pressure or the level of HbA1c        is reached.

A suitable type of feedback should be identified and developed. Theintention should be to develop an optimal type of feedback and normallythis is an iterative process. In this, the following aspects should beconsidered, as well as the concerns mentioned above describing what isincluded in the type of feedback:

-   -   The type of feedback should be designed based upon the specific        clinical circumstances of the pharmaceutical product concerning        the existence of possible adverse events, possible side effects,        and the therapeutic effect.    -   The type of feedback should be designed based upon the special        circumstances of the patient category of the actual therapeutic        area.    -   The type of feedback should be designed in order to improve the        behavioral aspects of the patients. They should increase the        possibilities for enhanced clinical effect and patient safety of        the specific pharmaceutical product, and the quality of life for        the patients.    -   It should be defined which type of feedback that should be given        and to whom.    -   The type of feedback should be designed and developed based upon        to whom and which type of feedback that should be given.    -   The type of feedback should be designed and developed based upon        the developed set of questions and set of functions for the        specific question-feedback model, QFM.    -   The type of feedback could be designed in order to improve the        clinical effect and patient safety of the specific        pharmaceutical product in using the given thresholds    -   The type of feedback could be designed in order to improve the        clinical effect and patient safety of the specific        pharmaceutical product by individualizing the dosage        administration of the specific pharmaceutical product to the        conditions of the patient

The question-analysis-feedback model, QAFM, comprises the followingparts:

-   -   A set of questions, which contains identical logical parts,        structure and aspects, as well as an identical development        process, as the one described above for the QFM    -   A set of functions, which contains identical logical parts,        structure and aspects, as well as an identical development        process, as the one described above for the QFM    -   The type of feedback, which contains identical logical parts,        structure and aspects, as well as an identical development        process, as the one described above for the QFM    -   The included QFM:s

Examples on differences between the QAFM and the QFM are, the list beingillustrative and non-exhaustive:

-   -   The set of questions within the QAFM should be adapted for all        included pharmaceutical products and their adapted QFM:s.    -   The type of questions given to the respondents, as well as the        performed analysis, the set of functions and the type of        feedback, are adapted to the specific characteristics of all the        included the pharmaceutical products, the therapeutic area(s)        and the behavior of the patients in order to improve the        clinical effect, patient safety and quality of life of the        patients. The set of functions could be used as an analysis        component evaluating all the included components within the QAFM        in order to improve the clinical effect, the safety and quality        of life of the patients. For example, the results of the        analysis by the set of functions could result in a        recommendation to the users to reduce the use of one component,        such as the dosage of an included pharmaceutical product and        instead increase the usage of another component, such as        increase the dosage of another pharmaceutical product.

The set of functions, as well as the type of feedback, in the QAFM mayrelate to the following, the list being illustrative and non-exhaustive:

-   -   Evaluation aspects of the included pharmaceutical products and        their corresponding QFM:s, based upon perceived clinical effect        and side effects/adverse events.    -   Evaluation in order to improve the clinical effect, the patient        safety and patient quality of life    -   Evaluation and feedback to the users in order to optimize the        included components for the specific patient based upon his/her        behavior and adherence to included components    -   Evaluation of patient specific information according to the        above, in relation to existing clinical information, i.e. data        from earlier performed clinical studies and clinical practice,        concerning the included pharmaceutical products

When developing the QAFM set of questions, the set of functions and thetype of feedback considerations should be done in order to optimize thetotal questionnaire and the feedback for the simplicity of the patients.The development of the QAFM will be iterative and similar to thedevelopment of the QFM, clearly adding the further aspects of the QAFMin relation to the QFM, such as the evaluation of the pharmaceuticalproducts and their adapted QFM:s.

It may be desirable to furthermore optimize the set of questions and thefeedback for use on a certain computer platform. For instance, if therespondent will use a simple mobile telephone the questions will beadapted so that they can be answered simply by pressing buttons 0-9 andyes/no/up/down and feedback may be provided in short text messages andsimple graphs. If the respondent uses an advanced mobile telephone ortablet computer the questions may be constructed to give more complexanswers and still be easy to use, and the feedback may also be made morecomplex, such as color-coded graphs and longer messages.

The candidate QAFM including the QFM:s is then validated in one or moresteps. The validation of the model aims to evaluate and ensure thetherapeutic effect of the integrated combination of the computer programproduct and pharmaceutical products, minimize the amount of adverseevents and side effects, and increase the quality of life for thepatients. The evaluation of the clinical effect and the value of thecandidate QAFM including the QFM:s for specific pharmaceutical productsare preferably performed through clinical trials, which is usuallyreferred to as a Phase II clinical trial or a corresponding study. Inthis the candidate model for the pharmaceutical products is evaluatedregarding clinical efficacy such as positive medical effect andincreased security level for the combination product.

There are a number of types and designs of clinical studies and askilled person will be able to choose a type of study and design wellsuited to achieve the aims as outlined herein. The clinical studies orcorresponding study will be designed to focus to prove the following ofthe model enabling the combination of the computer program product andthe pharmaceutical products:

-   -   achieve improved clinical effect of the combined product based        on the invention    -   achieve improved level of safety for patients    -   increase quality of life for the patient

Based on progress and results from clinical studies and clinicalpractice, the QFM and QAFM may of course be adjusted or revised in orderto improve its clinical effect, safety or aspects of quality.

The combination of the models and pharmaceutical products may also becompared to existing approved treatments in Phase III-type clinicaltrials before being put on the market.

The question-feedback model, and the question-analysis-feedback modelare implemented in one or more computer-program products running on oneor more computer platforms, wherein the computer program product and thecomputer platform together have means for providing the set ofquestions, for receiving the answers, for applying the analysis and theset of functions to generate the patient-specific feedback andpreferably also for providing said feedback to the patient.

The computer program product may be supplied on a suitable carriertogether with the pharmaceutical product, as a kit-of-parts. Suitablecarriers are well-known to the skilled person and depend on the platformon which the computer program product shall run, but includes withoutlimitation, CD-ROM, USB-memory sticks, flash memory cards. The computerprogram product may also be made available to the end user separatelyfrom the physical pharmaceutical product. This can be done e.g. bysupplying information on how to access the computer program product on aremote server and install the computer program product on the relevantplatform with the pharmaceutical product. The computer program productcan also be run on a remote server and be accessed via an internetservice using a user interface like a web browser or client applicationfor the relevant platform. Ways of accessing and implementing thecomputer program product can also include barcode scanning techniques.The computer program product may be included in the kit-of-parts in theform of instructions for accessing and/or installing the computerprogram product from a remote location, such as a remote server.Information about how to get started with the computer program productand how to use it can be given in the instructions related to thepharmaceutical product or the computer program product.

If the computer program product is made available separately from thepharmaceutical product, a unique identifier may be provided with eachindividual kit. The identifier may be used to confirm that therespondent has got the correct combination of computer program productand pharmaceutical product and to confirm that the respondent has theright to use the computer program product.

The computer program product is an essential part of the main aspect ofthe invention and is itself one aspect of the invention, as is themethod implemented in the computer program product.

The pharmaceutical product may be any pharmaceutical product for whichthere exists a preferred or prescribed administration and/or dosageregimen. This includes all pharmaceutical products that have beenapproved for marketing based on results of clinical trials defining atherapeutically effective dose or dose range and pharmaceutical productsfor which a medical or other practitioner prescribes an individualadministration or dosage regimen to an individual patient based oninformation supplied by the manufacturer of the pharmaceutical product.It furthermore includes pharmaceutical products for which an applicationfor marketing approval is to be submitted, pending, or has been refused.The pharmaceutical product may or may not be subject to regulation by aMedical Products Agency or other governmental agency, it may be aprescribed medication, an over-the-counter product or any otherallegedly therapeutically active product, such as a herbal medicinalproduct.

Examples of pharmaceutical products that can be used in the presentinvention are, the list being illustrative and non-exhaustive (tradenames within parentheses): Aripiprazol (Abilify), Rimonabant (Acomplia),Pioglitazon (Actos), glucoseamine (Glucosine), Octocog alfa (Advate,Advair), Flutikason in combination with Salmeterol (Seretide), zolpidem(Ambien, Stilnox), Insulin glulisin (Apidra), Donepezil (Aricept),irbesartan (Avapro, Aprovel), rosiglitazone (Avandia), metformin incombination with rosiglitazone (Avandamet), glimepiride in combinationwith rosiglitazone (Avandaryl), bevacizumab (Avastin), Interferon beta(Avonex), Darbepoetin alfa (Aranesp), anastrozole (Arimidex),Kandesartan (Atacand), olmesartan (Benicar, Olmetec), Interferon beta-1b(Betaseron), Interferon beta (Betaferon), exenatide (Byetta),Bikalutamid (Casodex), Celecoxib (Celebrex, Celebra), Escitalopram(Cipralex/Lexapro), duloxetine (Cymbalta), Vareniklin (Champix),Glatiramer (Copaxone), Carvedilol (Coreg), Losartan (Cozaar),Rosuvastatin (Crestor), Ramipril (Tritace), Valsartan (Diovan),Venlafaxin (Efexor), oxaliplatin (Eloxatin), Etanercept (Enbrel),raloxifene (Evista), ezetimibe (Ezetrol, Zetia), Tamsulosin (Flomax,Flomaxtra, Urimax), fluticasone (Flovent, Flixotide), Alendronic acid(Fosamax), Gemcitabine (Gemzar), imatinib mesylate (Gleevec, Glivec),Trastuzumab (Herceptin), insulin lispro (Humalog), Adalimumab (Humira),Lopinavir/ritonavir (Kaletra), Sumatriptan (Imitrex, Imigran),Sitagliptin (Januvia), insulin glargin (Lantus), Fenofibrate (Lipanthyl,TriCor), atorvastatin (Lipitor), Insulin Detemir (Levemir), amlodipineand benazepril (Lotrel), Leuprorelin, (Lupron, Leuplin), pregabalin(Lyrica), rituximab (Mabthera, Rituxan), Telmisartan (Micardis),Esomeprazole (Nexium), amlodipine (Norvasc), insulin aspart (NovoLog,NovoMix, NovoRapid), repaglinid (NovoNorm), Rabeprazole (Pariet),paroxetine (Paxil, Seroxat), Pantoprazole (Protonix, Pantozol,Pantoloc), Clopidogrel (Plavix), pravastatin (Pravachol), Epoetin Alfa(Procrit, Eprex), takrolimus (Protopic), budesonid (Pulmicort),interferon beta-la (Rebif), sibutramin (Reductil), Infliximab(Remicade), Risperidon (Risperdal), Metoprolol (Seloken, Toprol),quetiapine (Seroquel), Tiotropium (Spiriva), budesonide and formoterol(Symbicort), Montelukast (Singulair), Docetaxel (Taxotere), Topiramat(Topamax), Emtricitabin and Tenofovirdisoproxil (Truvada), ezetimibe andsimvastatin (Vytorin), bupropion (Wellbutrin), Betametason incombination with Kalcipotriol (Xamiol) calcipotriene (Taclonex),simvastatin (Zocor), Sertralin (Zoloft), zoledronic acid (Zometa),Olanzapin (Zyprexa), cetirizine (Zyrtec), ticagrelor (Brilique).

The invention will now be described in relation to the appendeddrawings.

FIG. 1 shows a combination product (111) according to claim 1 whereinN=2, comprising two pharmaceutical products (100 ₁, 100 ₂) available toa patient/respondent (102), and a computer program product (110). Twosets of questions (106) and two sets of functions (108), one for eachQFM (103), together with a set of questions (107) and a set of functions(109) of the QAFM, for converting the answers to the questions intopatient feedback are implemented in the computer program product (110)running on a computer platform (112) having means (104) for interactingwith patient/respondent 102, i.e. posing questions and receiving answersto said sets of questions (106) and (107), from said patient (102) andsend the answer information to the sets of functions of the QAFM (109)and QFMs (108 i, 1082). The computer platform further has means (114)for receiving patient feedback from the sets of functions (108) and(109), and communicating said feedback to said patient (102).

FIG. 2 shows an alternative embodiment of the invention, wherein afurther respondent (102′) answers further sets of questions (106′) forthe QFM and (107′) for the QAFM through means (104′) for receivinganswers to said sets of questions from said further respondent. Theanswers to the sets (106′) and (107′) are then provided together withthe answers to the sets (106) and (107) to the sets of functions (108)for the QFM and (109) for the QAFM respectively to generate feedback topatient (102) through computer platform means (114) for receivingpatient feedback from the sets of functions (108) and (109) andcommunicating said feedback to said patient (102). Optionally, feedbackis also provided to the further respondent (102′), shown with a dottedline. The further respondent may be a person close to the patient, suchas a family member. The means (104′) for receiving answers from thefurther respondent may be implemented on a separate computer platform(112′), cf FIG. 3.

The example below serves to further illustrate the invention, provideexperimental support and enable the skilled person to implement theinvention. It shall not be construed as limiting the scope of theinvention, which is that defined by the appended claims.

EXAMPLES

Study 1

A study is to be performed according to the following description inorder to exemplify and show the clinical effect of the invention.

In the study the combination product, a computer program product (CPP)integrated with two pharmaceutical products (PP:s), using an adaptedquestion-analysis-feedback model (QAFM) and two question-feedback models(QFM:s), should be evaluated versus only the two separate PP:s. Thepurpose is to evaluate different aspects in order to show the effect ofthe invention. The objective of the study should be to evaluate theclinical effect of a combination of two PP:s and a CPP, in relation toonly the two PP:s. The integration in the combination product should bedone through a QAFM and two QFM:s. The actual therapy area is type 1diabetes and the effect variable should be the level of HbA1c. Theactual PP:s are Apidra and Lantus.

In the study the used model should consist of the following parts:

-   -   A set of questions for the QAFM and two for the QFM:s. Some of        the characteristics:        -   Developed based on the specific aspects of the PP:s and the            patient category.        -   One compulsory group of questions to be asked, which should            be given to all patients, and one optional group of            questions to be asked if they were relevant for the            individual patient.        -   The questions should be individualized depending on the            patients' specific conditions and situation. For example,            specific questions should be added or removed depending on            specific patient conditions.        -   Different type of questions, i.e. multiple choice, VAS, etc.        -   Both compulsory and optional questions to be answered.        -   The questions should be integrated with a question schedule            with response times. The response times should include            automatic reminders (alerts) in the CPP on the mobile phones            to remind the patients to answer the questions. The question            schedule should be developed so only the questions valid for            each response time show up in the CPP and be possible for            the patient to answer. This feature should secure that the            patients answer the right questions at the right time. The            question schedule should be individualized depending on the            patient's daily schedule.        -   The questions should be presented to the patient on the            patient's mobile phone. The illustration (see FIG. 1) shows            the user interface of the implemented questions and            feedback.    -   The sets of functions in the model. Some of the characteristics:        -   Calculations on the data, consisted of the answers from the            patients, in order to present patient specific information            in different graphs. Data from different questions should be            grouped together to visualize important relationships and            correlations between variables. Graphs should be constructed            to show development over time for chosen variables.        -   Calculations on the collected and non-collected data, which            should trigger reminders to the patients about continuously            answering the questions.        -   Algorithms enabling the question schedules.        -   Applications handling and securing that patient specific            information should only be viewed by authorized personnel.        -   Applications handling and securing that feedback should be            realized in different digital channels such as Internet and            messages.    -   Patient-specific feedback information (see FIGS. 4A-4C). Some of        the characteristics:        -   Should be developed based on the specific aspects of the            PP:s and the patient category.        -   Patient specific graphs based upon the collected answers            from the patients to the set of questions. Health care            personnel should have access to these patient specific            graphs, which they should use for giving feedback in            different ways to the patients.        -   The graphs should be constructed in a way where relevant            variables are matched together and plotted over time            according to the set of functions. This should show            interesting and valuable relationships and correlations that            will give both the patients and/or the healthcare personnel            a better understanding of the patients' situation and            development.        -   Patient specific messages sent to the patients regarding            their treatment and situation.        -   Patient specific messages sent to the patients with            reminders to continue answering questions when their            adherence to answer the questions have decreased or stopped.        -   Oral communication between health care personnel and the            patients based on the patient specific feedback information            generated by the CPP.

The development of the used model (QAFM and QFM) for the PP:s in thestudy should include mainly the steps described earlier in the detaileddescription and clinically relevant information of the specific PP:s andthe patient category. It is an iterative process (see FIG. 5) beforeoptimal models for the specific PP:s (see FIG. 6) have been developedwith the set of questions and feedback information (see FIG. 7) and thequestion schedules (see FIG. 8). As said earlier in the detaileddescription, many aspects and considerations need to be taken intoaccount when developing the specific model.

Overview Technical Implementation of the CPP

The technical realization and implementation of the CPP in the study isillustrated in FIG. 9. The patients should first be registered in thesystem by the health care personnel and after that the patients shoulddownload, via mobile internet, the mobile phone application to theirmobile phones. The mobile phone application will process, handle andpresent the questions and answers to the patient. The CPP will alsoconsist of a web client application which has the primary user interfacefor the health care personnel. A server application with a data basewill also be an integral part of the implementation of the CPP.

Diabetes is an auto-immune disease in which the body's immune systemdestroys the insulin-producing beta cells in the pancreas. This type ofdiabetes, also known as juvenile-onset or insulin-dependent diabetes,accounts for 10-15% of all people with the disease. People with type 1diabetes must inject themselves with insulin several times a day andfollow a careful diet and exercise plan.

Glycated hemoglobin (hemoglobin A1c, HbA1c, A1C) is a form of hemoglobinthat is measured primarily to identify the average plasma glucoseconcentration over prolonged periods of time. This serves as a markerfor average blood glucose levels over the previous months prior to themeasurement.

HbA1c is recommended by WHO (World Health Organization) as a test todiagnose diabetes. The American Diabetes Association recommends that theHbA1c should be below 53 mmol/mol (7.0%) for most patients.

Rapid-acting insulin begins working very quickly inside the body—usuallywithin 5 and 10 minutes. This type of insulin should be taken justbefore or just after eating. It operates at maximum strength for one totwo hours and duration is typically up to four hours. Rapid-actinginsulin's are very convenient because they allow diabetic patients toinject themselves, at the time, when they eat. Long-acting insulinshould be taken once a day at the same time each day to lower the bloodglucose.

The study objective is to evaluate the clinical effect of using thecombination product, the two PP:s and a CPP, in type1 diabetes incomparison of using only the stand-alone PP:s themselves. The measuredvariable should be HbA1c. The variable should be measured directlybefore the patients entered into the study and directly afterwards whenthey had concluded their participation.

The patients in the intervention group should be given the combinationproduct, meanwhile the patients in the control group will be given onlythe separate PP:s.

Primary variable: HbA1c.

Length of study: 6 months

Number of patients: 20 in the intervention group and 20 in the controlgroup Inclusion criteria: Diagnosed diabetes type1 with more than 53mmol/mol HbA1c. Access to a mobile phone capable of handling the usedCPP.

Used PP:s: Rapid-acting insulin; Apidra and a long-acting insulin;Lantus

The used set of questions can be seen in table 1. The differentquestions were grouped together in questions groups with correspondingresponse times (see table 2). Some of the questions were asked threetimes a week, some more seldom, and some were “spontaneous”, i.e.,always available for the patient to answer. The question regime,appeared to the patient, could be another than the one presented in thetable.

The set of questions for the QAFM is to be the following: 1-5, 8-16,20-23

The set of questions for the QFM of Apidra (the first PP) is to be thefollowing: 6, 7

The set of questions for the QFM of Lantus (the second PP) is to be thefollowing: 17-19

TABLE 1 Questions Question type and answer Question alternatives 1.“Have you been irritated at someone/something VAS 0-10 today?” 0 = Notat all irritated, 10 = Extremely irritated 2. “How focused are you atschool/work?” VAS 0-10 0 = Not at all focused, 10 = Very focused 3. “Howdid you sleep last night?” VAS 0-10; 0 = Very poorly, 10 = Very well 4.“For how long time have you exercised today?” Multiple choice: 0 min,1-20 min, 21-40 min, 41-60 min, More than 60 min 5. “How many bloodglucose levels have you Numeric checked today?” 6. “How many units ofApidra did you take at Numeric breakfast?” 7. “How many units of Apidradid you take at the Numeric meal?” 8. “When did you eat breakfast?”Multiple choice: Before 6 am, Between 6-8 am, Between 8-10 am, I didn'teat breakfast 9. “When did you eat lunch?” Multiple choice: Before 11am, Between 11 am-1 pm, Between 1-3 pm, I didn't eat lunch 10. “When didyou have dinner?” Multiple choice: Before 5 pm, Between 5-7 pm, Between7-9 pm, I didn't eat dinner 11. “What was your blood glucose levelNumeric approximately 1.5 hours after breakfast (mmol/l)?” 12. “What wasyour blood glucose level Numeric approximately 1.5 hours after lunch(mmol/l)?” 13. “What was your blood glucose level Numeric approximately1.5 hours after dinner (mmol/l)?” 14. “What was your blood glucose levelbefore Numeric breakfast (mmol/l)?” 15. “What was your blood glucoselevel before Numeric lunch (mmol/l)?” 16. “What was your blood glucoselevel before Numeric dinner (mmol/l)?” 17. “Did you take your Lantustoday?” Multiple choice: Yes, No, Probably, Probably not 18. “How manyunits of Lantus did you take today?” Numeric 19. “At what time did youtake your Lantus?” Numeric 20. “How do you feel?” VAS 0-10; 0 =Extremely bad, 10 = Extremely good) 21. “Your weight this morning?”Numeric 22. “How hard is it to have been diagnosed with VAS 0-10; 0 =Not at all difficult, type1 diabetes?” 10 = Extremely hard 23. “To whatextent has diabetes affected your VAS 0-10; 0 = Very much, 10 =activities during the week?” Not at all

TABLE 2 Question schedule Question group Response time (alerts from CPP)“Morning questions” Mondays and Thursdays at 10 am “Afternoon questions”Mondays and Thursdays at 3 pm “Evening questions” Mondays and Thursdaysat 9 pm “Weekly questions” Once a week on Fridays at 3 pm “Monthlyquestions” Once a month on Fridays at 3 pm “Spontaneous questions”Questions always available to answer

The feedback to the patients is crucial in order to achieve a positiveclinical effect of the combination product.

Both the healthcare personnel and the patients should have access toupdated graphs with the patient's specific feedback information based onthe collected answers. The graphs are constructed in a way whererelevant variables are matched together and plotted over time, examplesof matched variables are shown in table 3. An illustrative example of apossible patient's possible feedback graph is shown in FIG. 10. Examplesof possible feedbacks that could be given to the patients are presentedin table 4.

TABLE 3 Examples of grouping of variables in feedback graphs Grouping offeedback graphs Questions/Variables Blood glucose and “What was yourblood glucose level insulin at breakfast before breakfast (mmol/l)?”“How many units of rapid-acting insulin did you take at breakfast?”“What was your blood glucose level approximately 1.5 hours afterbreakfast (mmol/l)?” Sleep and blood “How did you sleep last night?”glucose “What was your blood glucose level before breakfast (mmol/l)?”

In the following, two patient studies are described (one performed andone prospective). In the patient cases a combination product of two ormore pharmaceutical products integrated with a mobile softwareapplication, respectively adapted specific QFM:s and QAFM to thepharmaceuticals, were used. For one of the combination products a studywas performed, for the other the study is prospective. In the studywhich was performed, there was a period as well when the patient wasusing some of the pharmaceuticals solely without the integration of themobile software application and the specifically adapted QFM:s and QAFM.

The examples showed the necessity to adapt the set of functions giventhe specific capabilities for the pharmaceuticals, such as differentlevels of adherence and adverse events; and whether it is critical ornot to warn the patient for particular registrations of a variable.

Study 2: Development of Combination Product Based on Brilique and ASAIntroduction

Development of a combination product based on the pharmaceuticalsBrilique and acetylsalicylic acid (ASA), specifically adapted QFM:s andQAFM with a dependent software application

-   -   a. Test objectives; improved cardiovascular symptoms measured as        level of mortality    -   b. Main intervention factors;        -   i. an improved administration and adherence of Brilique        -   ii. an improved adherence to ASA        -   iii. an improved level of physical activity    -   c. Follow-up variables: Level of mortality, adherence to        Brilique and amount of physical activity    -   d. Period of time using the combination product: None; is to be        initiated. This is an example of a combination product and a        possible test to prove the effect of the invention.

Set of Questions Brilique and ASA

The used set of questions for the specific QFM:s and QAFM in thecombination product based on Brilique and ASA is the following:

-   -   Adherence to        -   Brilique; The patient will be asked to answer a question            whether or not he/she will be adherent to Brilique; “I have            taken my Brilique this morning/this afternoon”. This            question will show up once a day in the software            application. No questions regarding dose will be given.        -   ASA; The patient will be asked to answer a question whether            or not he/she will be adherent to ASA; “I have taken my ASA            today”. This question will show up once a day in the            software application. No questions regarding dose will be            given.    -   Physical activity;        -   The patient will be asked initially to set up an individual            goal with the purpose of achieving an increased effect which            is possible to update during a test. The individual goal            will be set-up by the patient by answering the following            question: “Give your own personal goal for the physical            activity in number of minutes for one week”. The patient            will then be asked to continuously answer a question like            the following: “I have been exercising the following number            of minutes today: [number]”, as well.    -   Weight/BMI;        -   The patient will be asked to answer a question regarding            his/her actual weight.    -   Blood pressure;        -   The patient will be asked to measure his/her actual blood            pressure, either by himself/herself at home or at a clinic.            Afterwards he/she is able to register it in the software            application by answering a question concerning both the            systolic and diastolic pressure, and where he/she had            measured it; at home or at a clinic. It is possible for the            patient to change or update such already registered answers.    -   Blood glucose;        -   The patient will be asked to register the measured blood            glucose, if he/she has measured it. It is possible for the            patient to change or update such already registered answers.    -   HbA1c;

The patient will be asked to register the HbA1c after it has beenmeasured at a clinic. For the defined set of questions adherence toBrilique, adherence to ASA, physical activity and weight/BMI will beprioritized in order to gain effect for the patient. The prioritizationimplies that the feedback messages and also the visual feedback will befocused on these questions, resulting in higher frequency of showingthem, and the visual feedback will be prominent compared to the otherquestions.

Set of Functions Brilique and ASA

The set of functions for adherence to Brilique and to ASA, and therelated type of feedback, will be defined according to the followinglogic:

-   -   1. Ata level        -   Brilique: of more than 85% of the tablets of Brilique has            been taken during the last week, where the normally            ordinated amount of tablet per week is fourteen, implying            that no more than two missed tablets was missed, the patient            shall be given a green color of the visual feedback since            he/she will be regarded as adherent. In addition to that the            missed tablets must not be in a row, causing a gap, in order            for the patient to be regarded as adherent. Feedback            messages encouraging the patient to remain adherent shall be            given.        -   ASA: defined as a maximum of totally one missed occasion the            last week, a general type of feedback message will be shown            to the patient indicating he/she is adherent. The patient            will also be given a green color on the visual feedback.    -   2. Ata level        -   Brilique: of below 85%, but above 70% of the tablets of            Brilique has been taken the last week, in addition to that            the maximum missed tablets in a row was two, the patient            shall be given a yellow color of the visual feedback.            Feedback messages encouraging the patient to increase the            level of adherence to Brilique shall be given, but they            shall not be critical.        -   ASA: defined as of two or three missed tablets the last            week, the patient will be regarded as non-adherent but not            critical. Another type of message will be shown to the            patient. The patient will be given a yellow color on the            visual feedback.    -   3. Ata level        -   Brilique: of less than 50% of the tablets of Brilique has            been taken during the last week, or if the amount of missed            tablets in a row was three or more, the patient shall be            given a red color of the visual feedback.            -   Feedback messages encouraging the patient to promptly                increase the level of adherence to Brilique shall be                given, since the situation may be critical.        -   ASA: defined as four or more missed tablets last week, the            patient will be regarded as non-adherent and critical.            Another type of message will be shown to the patient. The            patient will be given a red color on the visual feedback.

The set of functions for physical activity are utilizing both personaland official goals, based upon the following structure:

-   -   1. The use of individual goals or not    -   2. The patient reaches his/her individual goal or not    -   3. The patient reaches his/her formal objectives or not    -   4. A mix of point two and three

The personal goal can, for the Brilique QFM, be defined as zero sincesome patients are ordinated not to be physically active during the firsttreatment period. After a period of time, the healthcare personnel mayupdate the goal to normal levels.

The patient will be shown feedback messages depending on which of theabove levels he/she has registered.

For weight/BMI feedback messages will be shown every second weekdepending on which of the following BMI levels the patient recently hasregistered during the last two weeks:

-   -   1. BMI between 20 and 25    -   2. BMI between 25 and 30    -   3. BMI between 30 and 35    -   4. BMI above 35

If the patient will have registered either a clearly decreasing orincreasing trend of the BMI, the patient will be given messagesconcerning the purpose of either maintaining the trend or trying tointerrupt it.

When the total number of patients in the test is exceeding one hundred,a change in frequency and type of messages for adherence to Brilique isperformed. For patient one hundred one up to patient two hundred, thefrequency of the given adherence messages will be lowered and the typeof messages will be a bit friendlier.

When the total number of patients in the test is exceeding two hundred,an evaluation concerning the frequency and type of given feedbackmessages for adherence will be performed by the set of functions. Theresult of the level of adherence for the first hundred patients will becompared to the result of the second hundreds of patients. If the firsthundred patients are more adherent to Brilique concerning the actualperiod of green status for the patients, than the others, the frequencyof given adherence messages will be as the used frequency for the firsthundred patient. If the second hundred patients are more adherent,frequency for the first hundred will be increased. The similarevaluation is done concerning the level of friendliness in the messages.

When the total number of patients in the test is exceeding threehundred, a similar evaluation concerning adherence optimization isperformed but in the opposite direction—given that the first hundredpatients were most adherent—i.e. the evaluated frequency for newpatients will be higher, i.e. more frequent, and the level offriendliness in the messages will be lower. If the second hundredpatients were the most adherent in the first place, this evaluation willinstead be against an even lower frequency and more friendly messages.

Corresponding evaluations is then performed, also de-coupling the levelof frequency and the level of friendliness in the messages, in order tooptimize the level of adherence to Brilique among the patients using thecombination product. When the number of patients is exceeding fivehundred a similar evaluation is performed concerning the illustration ofthe visual graph for the type of feedback for adherence, where differenttypes of illustrations are compared to each other in order to optimizethe level of adherence.

Similar evaluations, in order to optimize adherence, is performedregarding ASA. However, there will be no evaluations concerning theillustration of the visual graph for the type of feedback for adherenceto ASA. Instead, the illustrations will be evaluated and changedstrictly according to the Brilique evaluation.

When the total number of patients in the test is exceeding two hundred,the 65^(th) percentile of the registered average values of performedlevel of physical activity from this population, will be used as theofficial objective for physical activity instead of the original set-upvalue. For every new patient this official objective will continuouslybe updated in order to achieve a proper objective.

When the total number of patients in the test is exceeding five hundred,the official objective for physical activity will be structured, aswell, according to separate objectives for each month, based on theperformed registrations from patients in the test, starting from theinitiation of using the combination product. Hence, the officialobjective for physical activity will most probably be different for eachmonth for the new patients using the combination product.

When the total number of patients in the test is exceeding one thousand,the official objectives for physical activity will be structured, aswell, according to separate objectives for each week, based on theperformed registrations from patients in the test, starting from theinitiation of using the combination product. Hence, the officialobjective for physical activity will most probably be different for eachweek for the new patients using the combination product.

Type of Feedback Brilique and ASA

The following feedback components, controlled by the set of functions,will be given to the patient:

-   -   Individual, predefined messages to be shown in the software        application in the patient's mobile phone. The total amount of        messages may exceed two hundred-fifty. They are all kindly        designed.    -   A simple, illustrative individual graph per variable, showing        the registrations of the patient in relation to personal and        official objectives. Different amount of information will be        shown for different variables.    -   An image/symbol indicating the actual level for the health        status of each variable, illustrated as a circle with different        colors and numbers within, will be shown for the prioritized        variables.    -   A table showing an amount of the latest registrations will be        shown in the view of the variable. From this table some of the        variable registrations will be possible to update.    -   Reminders, which the patient will be given when he/she has        forgotten to register whether he/she has been adherent to the        specific pharmaceutical or not.    -   General, static information without any relation to given        answers from the patient. This contains information about the        disease, the symptoms and the treatment.

The feedback to the patient will be immediate in the sense that also thelatest registration will be able to affect the set of functions. Thisset-up will be verified in a small initial test prior to the example asimportant for achieving clinical effect, especially for the visual typeof feedback.

An example of a feedback message for a patient with a green statusregarding adherence to Brilique is: “It's good that you are takingBrilique as agreed upon with your doctor. By doing so you are decreasingthe risk for getting a heart attack.” Corresponding messages will beshown for adherence to ASA.

A visual graph illustrating the patient adherence to Brilique and to ASAthe last week will be showing a diagram with twenty-one differentsymbols for the actual seven days, fourteen for Brilique and seven forASA, since the patient shall take Brilique twice and ASA once a day.

If the patient doesn't answer the question whether he/she has taken thespecific pharmaceutical for a specific occasion, a red cross will beshown. If the patient will register that he/she took the pharmaceutical,a green tick is shown instead.

An example of an individual message for physical activity when thepatient has fulfilled both the personal and official objectives is:“Good job! By remaining at this level of physical activity, which youare at now, a longer period of time you will substantially decrease therisk of getting another heart disease.” The patient will be givenfeedback messages for physical activity with a similar frequency to thepatient as for adherence to Brilique and ASA.

A visual graph showing the actual achieved amount of physical activityper week the last month, for the patient will be shown in the softwareapplication. It is illustrated through different staples in relation toboth the personal goal and the official goal of the amount of physicalactivity.

Depending on the actual BMI level individual feedback messages shall beshown. Focus on the information in the messages is on food intake. Anexample of a message to a patient with BMI above 35 is: “Proper eatinghabits are a central part of your treatment since you have a risk forheart disease.”

A visual graph will be shown indicating the patient's actual BMI level,and in the background of the graph different colors with green for BMIless than 25; light yellow for BMI above 25 and less than 30; darkeryellow for BMI above 30 and less than 35; light red for BMI above 35.

For blood pressure, blood glucose and HbA1c only general feedbackmessages will be given to the patient without relation in the set offunctions to the actual registered patient values.

The messages will be focusing on general health, such as physicalactivity and food intake, but also mention blood pressure, blood glucoseand HbA1c in order to make the patient aware of them. For the threevariables visual graphs are to be shown for the actually registeredpatient values.

Since the test is to be initiated, no results exist at this very moment.

Study 3: Development and Test of Combination Product Based on Zoloft,Metformin and Januvia

Introduction

Development and test of a combination product based on Zoloft, Metforminand Januvia, their respectively specifically adapted QFM:s the QAFM anddependent software application

-   -   a. Test objectives; improve cardiovascular and diabetes symptoms    -   b. Main intervention factors;        -   i. Improved administration and adherence of Zoloft        -   ii. Improved administration and adherence of Metformin        -   iii. Improved adherence to Januvia        -   iv. increased well-being initiating an improved level of            physical activity    -   c. Follow-up variables: Weight and HbA1c    -   d. Period of time using the combination product: Five months.    -   e. Period of time using only two of the pharmaceuticals, i.e. no        combination product, prior to the period of using the        combination product: Four months

Set of Questions Zoloft, Metformin and Januvia

The used set of questions within the specific QFM:s and QAFM in thecombination product based on Zoloft, Metformin and Januvia was thefollowing:

-   -   Adherence to all of the three pharmaceuticals. The patient was        asked to answer questions whether or not he/she has been        adherent to:        -   Zoloft, and which dose the patient had taken; “I have taken            my Zoloft today with the dose 25 mg/50 mg/100 mg/150 mg or            200 mg”.        -   Metformin, and which dose the patient took; “I have taken my            Metformin today with the daily dose of 500 mg/1000 mg/1500            mg/2000 mg/2500 mg or 3000 mg”.        -   Januvia; “I have taken my Januvia today”.    -   Physical activity:        -   The patient was asked initially to set up an individual goal            with the purpose of achieving an increased effect. The            individual goal was set-up by the patient by answering the            following question: “Give your own personal goal for the            physical activity in number of minutes for one week”.        -   The patient was then asked to continuously answer a question            like the following: “I have been exercising the following            number of minutes today: [number]”.    -   Weight/BMI;        -   The patient was asked to answer a question regarding their            actual weight.    -   Blood glucose;        -   The patient was asked to register their measured blood            glucose, when he/she had measured it. It was possible for            the patient to change or update already registered answers.    -   HbA1c;        -   The patient was asked to register their HbA1c after it has            been measured at a clinic.    -   Depression and Anxiety, respectively;        -   The patient was asked to register the actual level of            perceived depression respectively actual level of perceived            anxiety at predefined occasions every second day. It was            also possible for the patient to answer the question when            he/she wanted. The questions were structured as a Visual            Analog Scale (VAS).    -   Stress;        -   The patient was asked to register the actual level of            perceived stress. The question did show up at predefined            occasions every second day. It was also possible for the            patient to answer the question when he/she wanted. The            question was structured as a VAS.    -   Three specific possible adverse events for Zoloft:        -   “Do you have severe skin rash in your mouth or tongue?            Extremely skin rash versus No skin rash at all” according to            a Visual Analogue Scale        -   “Do you experience symptoms such as itchy rash, respiratory            problems, wheezing or swellings in your face? Extremely much            versus Nothing at all” according to a VAS structure        -   “Have you been upset or confused; or had diarrhea, fever and            high blood pressure; or had excessive sweating and rapid            heartbeat? Extremely much versus Nothing at all” according            to a VAS structure    -   A possible adverse event for Metformin;        -   “Have you experienced unexpected loss of weight, severe            nausea or vomiting (malaise), uncontrolled sudden pain when            breathing or abdominal? Extremely much versus Nothing at            all” according to a VAS structure    -   A possible side effect for Metformin;        -   “Have you experienced diarrhea, decreased appetite, malaise            or abdominal pain particularly during the initial treatment?            Extremely much versus Nothing at all” according to a VAS            structure    -   Two possible adverse events for Januvia;        -   “Have you experienced severe and persistent abdominal pain?            Extremely much versus Nothing at all” according to a VAS            structure        -   “Have you experienced a severe allergic reaction, such as            rash, hives, and swelling of the face, lips, tongue and            throat which could cause breathing or swallowing            difficulties? Extremely much versus Nothing at all”            according to a VAS structure

All of the questions were equally prioritized, in order to gain effectfor the patent, except for HbA1c, Anxiety and Stress, the adverse eventsand side effects. The prioritization implied that the feedback messagesand also the visual feedback were focused on these questions, resultingin higher frequency of showing them, and the visual feedback wasprominent compared to the other questions.

Set of Functions Zoloft, Metformin and Januvia

The set of functions for adherence to all of the three pharmaceuticalsZoloft, Metformin and Januvia, and the related type of feedback, wasdefined according to the following logic. One occasion for Metformin wasdefined as a daily dose.

-   -   1. Ata level        -   a. Zoloft: defined as a period of only one missed occasion,            or less, to take tablet(s), i.e. not two missed occasions,            or more, taking tablets in a row, a general type of feedback            messages was shown to the patient every third day indicating            he/she was adherent. The patient was also given a green            color on the visual feedback.        -   b. Metformin: defined as a period of only one missed            occasion, or less, to take tablet(s), i.e. not two missed            occasions, or more, taking tablets in a row, and a maximum            of totally two missed occasions a week, a general type of            feedback message was shown to the patient every third day            indicating he/she was adherent. The patient was also given a            green color on the visual feedback.        -   c. Januvia: defined as a maximum of totally one missed            tablet the last week, a general type of feedback message was            shown to the patient every third day indicating he/she was            adherent. The patient was also given a green color on the            visual feedback.    -   2. Ata level        -   a. Zoloft: of two missed occasions to take tablets, or more,            in a row, the patient was regarded as non-adherent. Another            type of message was shown to the patient every third day.            The patient was given a red color on the visual feedback.        -   b. Metformin: defined as a period of maximum of two missed            occasions to take tablets in a row, or three missed            occasions the last week, the patient was regarded as            non-adherent but not critical. Another type of message was            shown to the patient every third day. The patient was given            a yellow color on the visual feedback.        -   c. Januvia: defined as of two or three missed tablets the            last week, the patient was regarded as non-adherent but not            critical. Another type of message was shown to the patient            every third day. The patient was given a yellow color on the            visual feedback.    -   3. Ata level        -   a. Zoloft: (Nothing)        -   b. Metformin: defined as a period of three missed occasions            to take tablets in a row or more, or totally four or more            missed occasions the last week, the patient was regarded as            non-adherent and critical. Another type of message was shown            to the patient every third day. The patient was given a red            color on the visual feedback.        -   c. Januvia: defined as four or more missed tablets last            week, the patient was regarded as non-adherent and critical.            Another type of message was shown to the patient every third            day. The patient was given a red color on the visual            feedback.

The set of functions for physical activity was utilizing both personaland official goals. The personal goal was able to update by the patientwhenever he/she wanted. The physical activity official goal was higherthan for both Brilique and only using Zoloft.

The patient was given feedback messages for physical activity using thefollowing structure:

-   -   1. The use of individual goals or not    -   2. The patient reaches their individual goal or not    -   3. The patient reaches their official goal or not

The patient was given individual feedback messages depending on which ofthe above levels he/she registered.

For weight/BMI feedback messages were sent dependent on which of thefollowing BMI levels the patient recently had registered during the lasttwo weeks:

-   -   1. BMI between 20 and 25    -   2. BMI between 25 and 30    -   3. BMI between 30 and 35    -   4. BMI above 35

Set of functions for Blood glucose, connected to the blood glucosequestion, was configured to detect possible hyperglycemia and/orhypoglycemia for the patient. A predefined amount of registrations abovea defined level for hyperglycemia or below another for hypoglycemiatriggered predefined messages.

If the patient registered blood glucose three times in a row exceeding15 mmol/L messages for hyperglycemia were shown to the patient andregistrations at only one occasion below 2.5 mmol/L a message forhypoglycemia was shown.

Set of functions for both Depression and Anxiety was configured todetect a predefined amount of registrations above a certain level of thevariable performed during a specific time interval; at least threeregistrations above the level eight during at least three days. Whenthat criterion was fulfilled a predefined message was shown to thepatient.

Set of functions for Stress and HbA1c didn't cause any feedback to thepatient.

Set of functions for the possible adverse events for Zoloft andMetformin was according to the following logic:

-   -   1. If any of the questions resulted in a registration on the VAS        exceeding level five on the ten grade scale, a message was shown        to the patient that he/she should contact his/her responsible        doctor and describe his/her situation    -   2. If any of the questions resulted in a registration on the VAS        exceeding level seven on the ten grade scale, a message was        shown to the patient that he/she should promptly contact his/her        responsible doctor and describe his/her situation

Set of functions for the possible adverse events for Januvia wasaccording to the following logic:

-   -   1. If any of the two questions resulted in totally three        performed registrations on the VAS exceeding level four on the        ten grade scale, a message was shown to the patient that he/she        should contact his/her responsible doctor and describe his/her        situation    -   2. If any of the questions resulted in a registration on the VAS        exceeding level six on the ten grade scale, a message was shown        to the patient that he/she should promptly contact his/her        responsible doctor and describe his/her situation

Set of functions for the side effect for Metformin was according to thefollowing step:

-   -   1. If the question resulted in a registration on the VAS        exceeding level seven on the ten grade scale, a message was        shown to the patient that he/she should contact his/her        responsible doctor and describe the situation

Type of Feedback Zoloft, Metformin and Januvia

The following feedback components, controlled by the set of functions,were given to the patients:

-   -   Individual, predefined messages shown in the software        application in the patient's mobile phone. The amount of        messages exceeded hundred and they were all kindly designed.    -   A simple, illustrative individual graph per variable, showing        the patient's registrations in relation to personal and official        objectives for the actual pharmaceuticals. The time scales        differed between the different variables.    -   An image/symbol indicating the actual level for the health        status of each prioritized variable, illustrated as a circle        with different colors and numbers within, were shown for the        prioritized variables.    -   General, static information without any relation to given        answers from the patient. The feedback to the patient was        immediate in the sense that also the latest registration should        be able to affect the set of functions.

An example of a feedback message to the patient with a green status onadherence to Metformin was: “It's good that you are taking Metforminaccording to prescription. By doing so you are improving your situationwith diabetes”. An example of an adherence message with red status was:“You shouldn't miss taking Metformin, it would help you with yourdiabetes”

An example of feedback message to the patient with a green status onadherence to Januvia was: “Last week you have been taking Januviacompletely according to your ordination—Good!” Corresponding messageswere used as well for Zoloft.

A visual graph illustrating the patient adherence to Zoloft, Metforminand Januvia the last week showed a diagram with twenty-one differentsymbols for the actual seven days, three for each day the patient issupposed to take the daily dose for the respective pharmaceutical. Ifthe patient didn't answer the question whether he/she had taken thespecific pharmaceutical for a day, or denied to take it, a red cross wasshown for the actual pharmaceutical. If the patient had registered thathe/she took the pharmaceutical, a green tick was shown instead in thediagram.

The patient was given feedback messages depending on which of the levelsof physical activity he/she registered. An example of a message when thepatient has reached the official goal: “Really good job with yourexercise! By being physically active your heart will be more powerfuland you will absolutely feel better”. Corresponding messages were alsoshown if the patient reached their personal goal, but since the officialgoal was relatively high, the most positive messages were given forthat.

A visual graph showing the actual achieved amount of physical activityper week, for the last two months, was shown in the softwareapplication. It was illustrated through different staples in relationboth to the personal goal and to the official goal of amount of physicalactivity.

Depending on the actual BMI level feedback messages were shown. Focus onthe information in the messages was food and physical activity. Anexample of a message sent to a patient with BMI above 35 was: “By losingweight you will get several positive effects such as improved bloodglucose control, reduced lipids and decreased blood pressure.”

A visual graph was shown indicating the patient's actual BMI level, andin the background of the graph different colors with green for BMI lessthan 25; light yellow for BMI above 25 and less than 30; darker yellowfor BMI above 30 and less than 35; light red for BMI above 35. When theset of functions triggered a condition of hyperglycemia for the patient,a corresponding message was shown: “You seem to have had a little toohigh value on blood glucose. Hence, think of both being adherent toMetformin and having a proper intake of energy. If you have anyquestions, you could contact your responsible doctor”.

When the set of functions triggered a condition of hypoglycemia, acorresponding message could be shown: “You seem to have low blood sugar.If you haven't already done it you should immediately take some sugar.If this frequently happens you should contact your responsible doctor”.

HbA1c registrations were illustrated in a graph, but didn't cause anyfeedback messages to the patient.

For the possible adverse events for Zoloft according to the set offunctions, the following message was shown to the patient if he/she hadfulfilled level one; “You seem to have . . . [the actual symptom] andshould contact your responsible doctor and tell him/her about yoursituation and how you feel.” If the patient fulfilled level two, thefollowing message was shown: “You seem to have . . . [the actualsymptom] and should promptly contact your responsible doctor and tellhim/her about your situation and how you feel, if you haven't alreadydone it.”

For the possible adverse event for Metformin according to the set offunctions, a corresponding message was shown to the patient if he/shefulfilled level one; “You seem to have had problem with your diabetesand should contact your responsible doctor and tell him/her about yoursituation and how you feel.” If the patient registered on level two, thefollowing message was shown: “You seem to have had severe problems withyour diabetes and should promptly contact your responsible doctor andtell him/her about your situation and how you feel.”

For the possible adverse events for Januvia according to the set offunctions, the following message was shown to the patient if he/she hadfulfilled the criteria for level one; “You seem to have . . . [theactual symptoms] and should contact your responsible doctor and tellhim/her about your situation and how you feel.” If the patient hadfulfilled the criteria for level two, the following message was shown:“You seem to have . . . [the actual symptoms] and should promptlycontact your responsible doctor and tell him/her about your situationand how you feel, if you haven't already done it.”

For the possible side effect for Metformin according to the set offunctions, a corresponding message was shown to the patient; “You seemto have had a side effect and should contact your responsible doctor andtell him/her about your situation and how you feel.”

Test Result Combination Product Zoloft, Metformin and Januvia

Baseline value before test; HbA1c: 51 mmol/mol and Weight: 90 kg

End value after test; HbA1c: 43 mmol/mol and Weight: 85 kg

During the actual period of time of using the combination product basedupon Zoloft, Metformin, Januvia and specifically adapted QFM:s and QAFMwith a dependent software application, the patient decreased 8 mmol/molin HbA1c implying a decrease of 16%. The actual dose of Zoloft andMetformin was changed once during the period, starting at respectively50 mg and 2000 mg, and ending on 25 mg and 1500 mg. The actual dose ofJanuvia was not changed during the period.

During the test period when the patient was only taking Zoloft andMetformin, i.e. full combination product was not used since the patientdid not use the software application and neither took Januvia, the HbA1cslightly rose 5% and the weight was stable.

1. A method of treating a respiratory disorder with a combination of Nsubstances, wherein N>1, with pharmaceutical activity against at least arespiratory disorder, in combination with a computer program productcomprising instructions causing a computer to perform a methodcomprising the steps providing a patient with a set of questionsaccording to a question schedule, wherein said set of questions isadapted to said combination of substances; providing a patient with N−1sets of questions according to N−1 question schedules, wherein each setof questions is adapted to one of the substances in said combination;collecting answers to said sets of questions from said patient;subjecting the answers to said set of questions adapted to saidcombination of substances to a set of functions, thereby generating afirst patient specific feedback information; subjecting the answers tosaid sets of questions each adapted for one of the substances in saidcombination, to N sets of functions, thereby generating a second patientspecific feedback information; providing said first and second patientspecific feedback to the patient.
 2. The method according to claim 1,wherein the computer program product comprises instructions causing acomputer to perform a method comprising the steps providing at least onefurther respondent in addition to said patient with a second set ofquestions according to a second question schedule, wherein said secondset of questions is adapted to the combination of substances and/or toat least one of the substances in said combination; collecting answersto said questions from said further respondent; subjecting said answersfrom said further respondent to a second set of functions adapted to thesecond set of questions and the combination of substances and/or to atleast one of the substances in said combination thereby generatingpatient-specific feedback information; providing said feedbackinformation to the patient and, optionally, to the further respondent.3. The method according to claim 1, wherein the computer program productcomprising instructions causes a computer to perform a method comprisingthe steps a) providing a patient and optionally a further respondentwith sets of questions according to a question schedule, wherein saidsets of questions are adapted to the combination of substances and/or toat least one of the substances in said combination; b) collectinganswers to said questions from said patient and optionally said furtherrespondent; c) subjecting said answers to a set of functions adapted forthe sets of questions and the pharmaceutical product thereby generatingpatient-specific feedback information; d) providing said feedbackinformation to the patient and optionally to the further respondent; e)extracting information from said answers and providing said informationto a database adapted for storing information collected during clinicaluse of said combination of substances; f) providing information storedin said database to a reviser subjecting the sets of questions and/orthe sets of functions to a revision based on said information stored insaid database; g) obtaining a revised set of questions and/or a revisedset of functions from said reviser; and h) repeating steps a)-g).
 4. Themethod according to claim 3, wherein said database is adapted forstoring information collected from more than one patient, preferably atleast 50%, such as at least 75% or substantially 100% of patients,clinically using said combination of substances in combination with saidcomputer program product.
 5. The method according to claim 3, whereinsaid revision is based on information collected from said patient and/orother patients clinically using said combination of substances incombination with said computer program product.
 6. The method accordingto claim 3, wherein said revision is based on information obtainedduring clinical trials of the substance and/or commercial use of thesubstance.
 7. The method according to claim 3, wherein said database isadapted to store information comprising one or more of: patientidentifier, respondent identifier, individual caregiver identifier,organizational caregiver identifier, substance identifier, substancecombination identifier, respondent answers, type and date of occurrenceof adverse events, type and degree of adverse effects of one or moresubstance or substance combination, probability of an adverse event,probability of an adverse effect, patient health status, patienthistory, patient family history, patient genetic information, prescribeddosage or administration regimen, drug-drug interactions, life-stylefactors.
 8. The method according to claim 1, wherein the clinicalrelevance of the combination of said set of questions and said set offunctions has been validated in clinical trials.
 9. The method accordingto claim 1, wherein said set of questions and said set of functions arerelated to patient compliance to a preferred or prescribed dosage and/oradministration regimen of said combination of substances.
 10. The methodaccording to claim 1, wherein said set of questions and said set offunctions are related to an indication of possible occurrence ordevelopment of an adverse event and/or side effect.
 11. The methodaccording to claim 1, wherein said set of questions and said set offunctions are related to the patient's quality of life.
 12. The methodaccording to claim 1, wherein at least a subset of the set of questionsis related to the actual administration; actual dosage; perceived and/ormeasured therapeutic effects; test results and/or perceived quality oflife.
 13. The method according to claim 1, wherein the method furthercomprises subjecting said answers to a set of functions specific for theset of questions and the pharmaceutical product thereby generating anupdated question schedule, wherein said set of functions optionally useComputer Adaptive Testing and/or Item Response Theory.
 14. The methodaccording to claim 1, wherein said set of functions include functionsselected from the group consisting of: calculations of target parametersand trend lines; prediction of development of a condition; rules andthresholds for defining when to give notifications.
 15. The methodaccording to claim 1, wherein said method provides feedback only to thepatient, or to the patient and to other individuals.
 16. The methodaccording to claim 1, wherein information from an inhaler used foradministration of the combination of substances is provided to at leastone set of functions, in addition to answers from the set of questions,to generate patient specific feedback.
 17. The method according to claim1, wherein the combination of substances comprises at least budesonideand formoterol.
 18. The method according to claim 1, wherein thecombination of substances comprises at least flutikason and salmeterol.19. The method according to claim 1, wherein the respiratory disorder isasthma or chronic obstructive pulmonary disease.
 20. The methodaccording to claim 1, wherein said computer program product is providedon a physical medium or by means or instructions for accessing andinstalling the computer program product on a computer.
 21. A kit ofparts comprising a combination of substances and a computer programproduct according to claim 1, wherein said computer program product isprovided by means or instructions for accessing and installing thecomputer program product on a computer and said kit further comprises anidentifier unique to the kit.
 22. A kit of parts comprising acombination of substances and a computer program product according toclaim 16, wherein the kit of parts comprises the combination ofsubstances, the computer program product, and an inhaler adapted toprovide information to at least one set of functions.